Lower Gastrointestinal Tract Dysfunction.
The lower gastrointestinal tract [LGIT] is the section of the digestive tract from the pylorus to the anus. The walls of the LGIT are organized into four main layers: mucosa, submucosa, muscularis externa, and serosa. The mucosa consists of an epithelium with basement membrane, loose connective tissue, blood vessels, nerve endings, and lymph tissues (together called the lamina propria). The submucosa further supports the mucosa and also contains loose connective tissue, glands, blood vessels, nerve endings, and bundles of nerves called Meissner's plexus. The muscularis externa consists of two bands of smooth muscle cells, an internal layer of circular smooth muscle and external layer of longitudinal fibers. Interspersed between the muscle fibers is the plexus of Auerbach. The outermost layer of the digestive tube, the serosa, is composed of a membrane of squamous epithelium. The enteric mucosa, unlike the skin, does not have a keratin layer, and is thereby “non-keratinizing tissue”.
The gut has a simplified “brain”. The nerve network in the mucosa, submucosa, and myenteric plexuses has about 100 million neurons (the enteric nervous system). The submucosal Meissner's plexus regulates secretion by intestinal glands. The myenteric Auerbach plexus controls the rhythmic contraction of circular and longitudinal muscles [peristalsis]. Visceral nerve afferents are located throughout the mucosa, submucosa and the Meissner's plexus and the neuronal cell bodies are either in autonomic ganglia or in dorsal root ganglia. The sensory information from the gut is conveyed mainly via the vagus and splanchnic/pelvic nerves entering the spinal nervous system. Visceral sensations of pain and discomfort are also transmitted via sympathetic afferents into the spinal cord.
When the gut does not work properly, key elements of dysfunction usually originate from the enteric mucosa and, within it, the intrinsic nervous system. The epithelia of the LGIT have high metabolic activity and a turnover rate of about 5 days; that is, within 5 days, the entire lining is shed and renewed. This is a turnover of about ¼ pounds of cells per day. Many LGIT disorders are characterized by depletion of or damage to mucosa resulting from exposure to toxins, inflammation, autoimmune diseases, infections, etc. Typical symptoms are diarrhea and abdominal pain, and in the case of ulcerative colitis frequent passage of fresh blood through the anus [hematochezia].
A functional disorder of the LGIT is the irritable bowel syndrome [IBS]. Two organic diseases are ulcerative colitis and Crohn's disease, referred to as inflammatory bowel disease [IBD]. Other LGIT disorders are diverticulitis, celiac disease, lactose intolerance, chronic pancreatitis and regional ileitis. The clinical signs and symptoms of LGIT disorders include abdominal pain, a sense of distension or bloat, muscle spasms, decreased or increased frequency of bowel movements, intra-luminal bleeding, and flatulence. The pathophysiology is due to the disruption of intestinal (enteric) mucosal function and local inflammation. Current treatment for IBD includes anti-inflammatory drugs such as glucocorticosteroids, 5-aminosalicyclic acid (5-ASA, mesazaline), anti-spasmodic agents, anti-α-TNF drugs, and anti-diarrheal drugs. Surgery to remove the affected tissues [colectomy] is also used when the IBD is advanced as in ulcerative colitis.
In IBS aromatic oils can relax smooth muscle and relieve pain caused by cramps and gas. Peppermint oil is the most common agent in this class. Enteric-coated capsules containing peppermint oil have beneficial effects in IBS (Capello et al., Digestive and Liver Disease Peppermint oil (Mintoil®) in the treatment of irritable bowel syndrome: a prospective double blind placebo controlled randomized trial. 39: 530-536, 2007). Peppermint oil is 30 to 55% menthol and it is thought that menthol is the active ingredient in peppermint oil. Colpermin®, enteric coated capsules of peppermint oil, is approved for sale in Europe and in the United Kingdom, but not in the United States. Some of the constituents of peppermint oil, for example, pulegone may be toxic to the liver. Peppermint oil also contain 15 to 30% of menthone, a mutagen in the Salmonella Ames test [Andersen, P. H., Jensen, N.J., 1984. Mutagenic investigation of peppermint oil in the Salmonella/mammalian-microsome test. Mutat. Res. 138, 17-20]. The menthol content of peppermint oil is thought to locally diminish smooth muscle contractility and to reduce afferent discharge of sensory nerve endings. The recommended dosage for Colpermin® is three capsules per day; side-effects include diarrhea.
The LGIT actions of menthol and icilin, both “non-selective” TRPM8 receptor agonists, have been studied [“non-selective” means actions on more than one receptor types]. TRPM8 nerve endings, detected by immunoreactivity, are present in the LGIT. Menthol relaxes smooth muscle preparations (e.g. guinea pig ileum, and human colon) by blocking calcium channels on smooth muscle, but the mechanism is not via TRPM8. Icilin, a potent TRPM8 agonist, produces a contractile response in mouse colon and jejunum [Penuelas et al. 2007. Contractile effect of TRPA1 receptor agonists in the isolated mouse intestine. Eur. J. Pharmacol. 576, 143-50]. Hosoya et al. [2014. TRPM8 has a key role in experimental colitis-induced visceral hyperalgesia in mice. Neurogastroenterol. Motil. 26, 1112-21] administered WS-12, a selective TRPM8 agonist, and elicited a “freezing reaction” in mice with colitis, indicating that WS-12 produced pain and hyperalgesia, which are undesirable effects in colitis. Ramachandran et al. [TRPM8 activation attenuates inflammatory responses in mouse models of colitis. Proc. Natl. Acad. Sci. U.S.A. 110, 7476-81, 2013] showed that icilin reduced inflammation in a mouse model of colitis, a result supported by DeJong et al. [TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP. Mucosal. Immunol. 8: 491-504, 2015] who observed that TRPM8 knockout mice have a greater sensitivity to colitis.
Agonists are drugs that activate biological systems. Antagonists are drugs that sit on a receptor, block its function, but do not have intrinsic action on the receptor. Ramachandran et al. and DeJong et al. make a case the use of a TRPM8 agonist in LGIT dysfunction. Penuelas et al. and Hosoya et al. make a case for use of a TRPM8 antagonist.
Watson et al. [Compounds with the Menthol Cooling Effect. J. Soc. Cosmet. Chem. 29: 185-200, 1978] and Rowsell and Spring [Phosphine oxides having a physiological cooling effect, U.S. Pat. No. 4,070,496, 1978] synthesized a number of cooling agents with the goal of finding applications in comestibles and toiletries. Some of the compounds made by Watson et al. are known to act as TRPM8 agonists [Behrendt, H.-J. et al. 2004. Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br. J. Pharmacol. 141: 737-45, 2004].